title: An expeditious access to 5-pyrimidinol derivatives from cyclic methylglyoxal diadducts, formation of argpyrimidines under physiological conditions and discovery of new CFTR inhibitors.
abstract: In the study of previously reported modulators of CFTR chloride channels that are cyclic methylglyoxal (MG) diadducts (CMGD) to aromatic α-aminoazaheterocycles, we optimized a new expeditious one pot route for preparing in water novel aromatic polycyclic azaheterocycles and described 5-pyrimidinols antioxidants through the formation of 2-oxoaldehyde diadducts to aromatic α-aminoazaheterocycles, amidines, guanidines and thiourea. In regard to the importance as biomarkers of diabetic complications of the 5-pyrimidinols "argpyrimidines" formed in proteins from MG and arginine residues, we demonstrated that argpyrimidines are slowly formed under physiological conditions from CMGD to arginine derivatives according to the synthesis route described. Among the 5-pyrimidinol derivatives prepared, two polycyclic derivatives appeared to inhibit strongly the activity of CFTR channels in wt-CHO cells.
authors.affiliation: University Joseph Fourier-Grenoble 1/CNRS, UMR 5063, Département de Pharmacochimie Moléculaire, ICMG FR 2607, Bât. E 470 rue de la Chimie, BP 53 F-38041, Grenoble Cedex 9, France.
authors.forename: Brice-Loïc
authors.initials: BL
authors.lastname: Renard
authors.forename: Benjamin
authors.initials: B
authors.lastname: Boucherle
authors.forename: Bruno
authors.initials: B
authors.lastname: Maurin
authors.forename: Marie-Carmen
authors.initials: MC
authors.lastname: Molina
authors.forename: Caroline
authors.initials: C
authors.lastname: Norez
authors.forename: Frédéric
authors.initials: F
authors.lastname: Becq
authors.forename: Jean-Luc
authors.initials: JL
authors.lastname: Décout
mesh_terms: D000818:Animals; D016466:CHO Cells; D002627:Chemistry, Physical; D006224:Cricetinae; D003412:Cricetulus; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000037:antagonists & inhibitors*; D055808:Drug Discovery; D008968:Molecular Conformation; D009952:Ornithine / Q000031:analogs & derivatives* / Q000737:chemistry; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011765:Pyruvaldehyde / Q000031:analogs & derivatives / Q000737:chemistry*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D011743:Pyrimidines; C107313:argpyrimidine; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D011765:Pyruvaldehyde; D009952:Ornithine